Failure to thrive, the doctors called it. Maddeningly unspecific. There wasn't much they could do. "I don't think they thought he would live," recalls Gallagher. "He was so lifeless." It was agreed that Gallagher could take her son home, as she wished—provided she brought him back every few days to be weighed.

"I had to set up an alarm clock next to my bed to wake him up to feed him," she recalls of those earliest days. The baby couldn't breastfeed or suck a bottle, so she cut the end off a preemie nipple, "and basically poured the formula down his throat." After three-and-a-half weeks Kyle had gained strength enough to suckle.

Still there were no strong clues as to what was wrong with him. They had been referred to a neurologist, whose ongoing diagnosis "was just describing the symptoms," Gallagher says. Hypotonia—lack of muscle tone, or "floppiness"—and developmental delay. "The doctor led us along, so sure he knew what it was, but we never really got down to the details. He never really answered our questions."

By six weeks, Gallagher could stand the uncertainty no longer. She began to hunt for answers on her own, making phone calls, haunting libraries, tracking through medical journals. Searching for any kind of lead.

Little by little, she began piecing things together.

By about three months, she remembers, she had it figured out. Kyle had a rare genetic disorder called Prader-Willi syndrome. She was sure of it.

The neurologist was sure she was wrong.

"I argued with him for a year and a half," Gallagher says, growing warm at the memory. At the same time she was asking other people about Prader-Willi—other doctors, friends who were nurses, practically everyone she met. No one had even heard of it.

Even after Kyle had begun to put on weight, the classic sign of the disorder, her neurologist refused to believe the child had Prader-Willi.

At last, despite his insistence that she was wasting her money, the doctor okayed chromosomal testing for Kyle. This should settle it once and for all.

The test came back showing no abnormalities.

Many Prader-Willi parents have had a similar experience. The syndrome, named for the two Swiss doctors who first reported it in 1956, is a non-inherited genetic disorder— the result of a defect in chromosome 15, specifically a region of the chromosome that is contributed by the father. It occurs in 1 in 15,000 live births, causing short stature, a severe lack of muscle tone, mild to moderate mental retardation, and a variety of other physical and behavioral problems. Most strikingly, however, Prader-Willi causes acute hyperphagia—a literally insatiable appetite.

"Persons with Prader-Willi syndrome think, talk, and dream food 24 hours a day," warns a pamphlet provided to physicians by the national Prader-Willi Syndrome Association. If uncontrolled, Prader-Willi patients can, in the language of TV talk shows, eat themselves to death: developing morbid obesity in early childhood with severe complications involving the heart, lungs, and other organs. There is no cure for the disorder, only management—a 24-hour-a-day job centering around strict control of eating behavior. "The way you hear about this disorder," says Maria Mascari, a medical geneticist at Penn State's Milton S. Hershey Medical Center, "is through stories about parents putting locks on the refrigerator."

The best strategy, experts say, is to try to prevent uncontrolled eating—and obesity—from getting established in the first place, which means the earlier the diagnosis the better. Unfortunately, early diagnosis of Prader-Willi has been a very iffy business.

The reasons are complicated. For one thing, the disorder reveals itself slowly, in two markedly different stages. In those early days when Barbara Gallagher was scouring medical journals for clues to her infant son's strange torpor, she remembers, "I couldn't imagine him having an eating problem." Suddenly, sometime after one year, the child begins to eat— at last, to thrive. For baffled, heartsick parents it seems at first a godsend, and by the time they realize that the problem has merely changed shape, the child may be well on the way to obesity.

Many physicians, moreover, are too unfamiliar with Prader-Willi to see what they're looking at. The syndrome is rare. And its recent emergence means, as Mascari's Penn State colleague Peter Rogan says, that "There's still a whole generation of physicians out there who didn't get this in medical school."

The result has too often been a nightmare for everyone involved. "You hear these horror stories," Mascari says. "I have met with families whose children were not diagnosed until they were 25, or even 35. One daughter was 40 years old!"

Even when a physician knows enough to request genetic testing, traditional tests frequently provide no definitive answer. Although the majority of Prader-Willi patients exhibit a characteristic malformation on the paternal 15th chromosome, up to 40 percent of those afflicted show no such abnormality. As in the case of Kyle, the chromosomes of this large minority of patients appear perfectly normal.

M. Scott Johnson

Mascari began to notice a number of such patients shortly after she arrived at Hershey in 1985 and began working at the Medical Center's Genetics Clinic. Fresh from completing a master's degree in genetic counseling, she was looking for a Ph.D. project that would allow her to continue working with patients and their families. This question about Prader-Willi intrigued her, as it did many geneticists, and the availability of interested parents and patients clinched the decision. Here, certainly, was a significant clinical question, and one she might be able to answer.

Mascari began investigating techniques for molecular analysis, tools far more refined than the standard chromosomal tests. Instead of trying to spot gross differences between whole chromosomes—removed from blood cells and then stretched, dyed, and magnified—she would zoom in on specific regions, examining at the level of DNA base pairs. Molecular technology would allow her to pick up exceedingly tiny defects that broader studies couldn't hope to spot.

She worked for a year to master the intricacies of the new techniques, meanwhile negotiating, with the help of Roger Ladda, chief of the genetics division at Hershey, with Ladda's colleague Sam Latt, now deceased but then at Children's Hospital in Boston, for access to specific DNA probes that Latt had painstakingly developed for Prader-Willi. Once the probes had been secured, in July 1988, it took another year of work to learn how to use them.

Toward the end of this latter period, another of Latt's collaborators, Robert Nicholls of the University of Florida, announced in Nature a surprising solution to the Prader-Willi riddle. Using the same probes that Mascari was trying to tame, with a considerable head-start, Nicholls had looked closely at two Prader-Willi patients with "normal" pairs of chromosome 15. In both cases he found that the individual chromosomes were in fact normal. The problem was, in each case both 15s had come from the child's mother! Neither patient had received a copy of chromosome 15 from the father.

The phenomenon Nicholls described, called maternal disomy, had been simply unknown before 1980. It was considered exceedingly rare, especially in humans. For Mascari, the question had changed. Could this oddity really be the cause of a significant number of those genetically unexplained cases of Prader-Willi?

At a professional meeting in San Diego in late 1989 she met Nicholls and the two agreed to collaborate on a study. Together, they gathered a sample of 30 patients with classic Prader-Willi characteristics but no readily apparent chromosomal damage. Mascari took the blood samples and ran the DNA analyses.

Four patients, they found, still showed no abnormality. Eight showed subtler versions of the standard chromosomal defect. The remaining 18 patients showed the presence of maternal disomy.

Mascari and Nicholls published their findings in the New England Journal of Medicine. For Mascari, the "main benefit" of this initial project was clinical: the work means 95 percent of the syndrome's sufferers can now be pinpointed by genetic testing. In terms of understanding inheritance, the ramifications could be even larger.

Uniparental disomy, the receipt of both chromosomes from one parent, has now been observed in chromosomes 4, 6, 7, 11, 14, 16, and 21, as well as in 15. It has been implicated in at least 10 other genetic syndromes along with Prader-Willi. No one knows exactly how often it occurs, but uniparental disomy's "emergence" is forcing geneticists to reevaluate some of the basic concepts of inheritance. Already, there have been two cases described of cystic fibrosis—a recessive disorder normally requiring both parents to be carriers—in children whose father did not carry it. "The mother passed on two copies of the same chromosome—the bad one," Mascari explains.

What could cause both chromosomes to come from one parent? Signs point to an error of chromosome segregation during the forming of the egg.

An egg cell is formed by a special process of cell division called meiosis. The pairs of chromosomes in the original cell split, one member of each pair going to a new egg cell. The egg, with its 23 single chromosomes, eventually meets with a sperm cell, which also has only 23 singles, and the two join, becoming one fertilized cell with a full set of 23 pairs, each pair ideally including one chromosome from each parent.

Sometimes, however, things get tangled. Literally. Just before the original split, each chromosome pair is engaged in the important evolutionary business of recombination, or crossover, a process of swapping genes back and forth. "This exchange of material serves to mix up the genome," Mascari explains, "so that you get a mixture of your mother's two chromosomes in the one she gives you, and likewise for your father."

In some cases—especially, Mascari has found, where the mother is older—there's too much of a good thing. The system weakens somehow. Recombination gets out of control, and the chromosomes can't manage to resolve themselves. "It's like trying to untangle a knot," Mascari says. "In those circumstances," Rogan adds, "you're more likely to have non-disjunction."

Non-disjunction means a pair of chromosomes doesn't split as it should: consequently one of the daughter egg cells gets both chromosomes and the other gets nothing. If the short-shrifted egg meets a sperm, the result is monosomy—a cell that is one chromosome shy of the full 46. The other egg, fertilized, ends up with one chromosome too many—a triplet of the affected member instead of a pair.

This triplet, or trisomy, has grave consequences. Its occurrence in chromosome 21 leads to Down's syndrome. When it happens in chromosome 15, the aberration is usually lethal. Sometimes, however, in a curious adjustment geneticists call "selection for life," the fatal redundancy is somehow lost early in development. Two-thirds of the time, following random selection, it will be one of the mother's 15s lost, and the pregnancy will return to normal. In that one-third of cases where the father's lone contribution is lost, on the other hand, the result is maternal disomy—and Prader-Willi.

The concept of maternal disomy is more than a curiosity. For geneticists, the evidence it provides of a difference between "male" and "female" genes is flatly revolutionary. According to standard laws of inheritance, a gene should behave the same way no matter where it comes from. In the case of Mendel's peas, the inherited trait of roundness will be expressed whether contributed by the "mother" plant or by the "father." This law of equivalent crosses had been held as inviolable for nearly 150 years. But uniparental disomy reveals numerous cases, both plant and animal, where the rule simply doesn't apply. And in humans, the clearest such case involves Prader-Willi.

Prader-Willi, it turns out, has a sister disorder, called Angelman syndrome. Angelman's symptoms are very different from those of Prader-Willi, including severe mental retardation, jerky movements and escessive laughter. Yet, like Prader-Willi, Angelman is traceable to the absence of crucial genetic information on chromosome 15. The difference is this: With Angelman, it is the maternal genetic information that is missing.

Thus, the two syndromes create a kind of mirror image: An individual who inherits both chromosome 15s from the mother gets Prader-Willi; one who gets both of that same chromosome from the father gets Angelman.

To a geneticist, the obvious question is, "Why should there be a completely different phenotype?" I.e., why should the switching of one chromosome 15 for another produce such different results? After all, "It's basically the same genetic information," says Mascari. "We all carry the same set of genes, in the same order.

"What it reflects is a differential expression of genes, depending on which parent they come from." And what that suggests is that the genes are not alike after all. In some subtle way that we can't yet detect they are marked—imprinted—to behave differently.

Nobody knows just how many human traits may be affected—controlled—by genetic imprinting. But a flurry of recent work shows evidence of imprinting in certain childhood cancers and neurologic diseases as well as in chromosomal syndromes. And there are suggestions that these effects may be only the tip of the iceberg. In mice, Mascari notes, "We now think that as much as 70 percent of the genome is imprinted."

Barbara Gallagher suspects her son "would probably be a classic case" of maternal disomy, but Kyle has never undergone molecular genetic testing. "We don't really care why it happened at this point," she explains. Still, having the molecular test available might have made it easier for her and her family in the early days—if nothing else, easier to convince their doctor that Kyle did indeed have Prader-Willi.

Kyle was eventually diagnosed, at two-and-a-half, by pediatric geneticist Suzanne Cassidy, then at the University of Connecticut, one of the syndrome's leading clinicians. Gallagher found Cassidy through the national Prader-Willi association.

Kyle is seven now, and he and his family continue to struggle against the effects of his disorder every day—dealing with problems that range far beyond compulsive eating.

"He didn't walk until he was close to three-and-a-half," Gallagher says. From two months to 18 months old he was enrolled in an infant stimulation program, and from 18 months to six years, in a therapeutic preschool. Now, "he gets around, but he wears out quickly." Lack of muscle tone means his muscles don't hold his bones together properly, which means joints can be easily damaged. He has had to wear splints to brace his fingers for writing, and corrective shoes, and "he has to try to keep himself together—he braces himself when you get ready to pick him up." Lack of muscle tone has also affected his speech, requiring therapy. He has undergone several eye surgeries for syndrome-related problems.

Despite these hardships, Kyle is mainstreamed in a first-grade class at the local elementary school, and he played T-ball last year in Little League. "He tries his absolute best," Gallagher says, "and that helps him out a lot." He even eats in the school cafeteria, albeit his own, closely regulated diet.

"He knows what he's allowed, and he has a fixed routine. He accepts that," Gallagher says, adding: "The thing is, he's never been allowed to eat all he wants. Because of the early diagnosis we were able to control him from the start." The eating behaviors associated with the disease, she knows, tend to worsen with age. "But right now, that's not really the big problem for us."

There remain cases, she knows from talking to other parents of children with Prader-Willi, of families searching years for a diagnosis. "This is not just in hick towns," she says. "They're running in and out of big-city hospitals. It just isn't diagnosed unless the child is obese or has severe mental problems. But those are the old criteria. Doctors need to get up to date."

Mascari agrees. Many Prader-Willi patients still are not diagnosed by a physician, she notes. "A mother will read an article in one of the women's magazines, or see it on a talk show." In the past five years, however, she adds, awareness of Prader-Willi has improved "tremendously." In February of this year, the journal Pediatrics published a new consensus of diagnostic criteria. Suzanne Cassidy was one of the authors.

Mascari serves on the board of the Prader Willi Syndrome Association of Pennsylvania, which has been active in the education effort. Since publication of her study in the New England Journal, the Hershey Medical Center has opened a Prader-Willi clinic, for which she serves as genetics counselor. Already, the clinic receives requests for molecular-testing from all over the country—for Prader-Willi and for Angelman syndrome too.

"We now get referrals for testing to rule out Prader-Willi," Mascari says. "We've had them for patients as young as a few days old."

Maria J. Mascari, Ph.D., is instructor in the division of genetics, department of pediatrics, in the College of Medicine, The Milton S, Hershey Medical Center, Pennsylvania State University, 500 University Drive, Hershey, PA 17033; 717-531-8414. She is also coordinator and genetic counselor for the Medical Center's Prader-Willi Syndrome Clinic. Peter K. Rogan, Ph.D., is an assistant professor in the division of genetics. The work reported above was funded by grants from the March of Dimes Birth Defects Foundation and the American Heart Association.